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Patricia A Labosky - One of the best experts on this subject based on the ideXlab platform.
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neural crest and schwann cell progenitor derived melanocytes are two spatially segregated populations similarly regulated by FOXD3
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Erez Nitzan, Elise R Pfaltzgraff, Patricia A Labosky, Chaya KalcheimAbstract:Skin melanocytes arise from two sources: either directly from neural crest progenitors or indirectly from neural crest-derived Schwann cell precursors after colonization of peripheral nerves. The relationship between these two melanocyte populations and the factors controlling their specification remains poorly understood. Direct lineage tracing reveals that neural crest and Schwann cell progenitor-derived melanocytes are differentially restricted to the epaxial and hypaxial body domains, respectively. Furthermore, although both populations are initially part of the FOXD3 lineage, hypaxial melanocytes lose FOXD3 at late stages upon separation from the nerve, whereas we recently found that epaxial melanocytes segregate earlier from FOXD3-positive neural progenitors while still residing in the dorsal neural tube. Gain- and loss-of-function experiments in avians and mice, respectively, reveal that FOXD3 is both sufficient and necessary for regulating the balance between melanocyte and Schwann cell development. In addition, FOXD3 is also sufficient to regulate the switch between neuronal and glial fates in sensory ganglia. Together, we propose that differential fate acquisition of neural crest-derived cells depends on their progressive segregation from the FOXD3-positive lineage.
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Loss of FOXD3 Results in Decreased β-Cell Proliferation and Glucose Intolerance During Pregnancy
Endocrinology, 2011Co-Authors: Jennifer L. Plank, Audrey Y. Frist, Alison W. Legrone, Mark A. Magnuson, Patricia A LaboskyAbstract:A complete molecular understanding of β-cell mass expansion will be useful for the improvement of therapies to treat diabetic patients. During normal periods of metabolic challenges, such as pregnancy, β-cells proliferate, or self-renew, to meet the new physiological demands. The transcription factor Forkhead box D3 (FOXD3) is required for maintenance and self-renewal of several diverse progenitor cell lineages, and FOXD3 is expressed in the pancreatic primordium beginning at 10.5 d postcoitum, becoming localized predominantly to β-cells after birth. Here, we show that mice carrying a pancreas-specific deletion of FOXD3 have impaired glucose tolerance, decreased β-cell mass, decreased β-cell proliferation, and decreased β-cell size during pregnancy. In addition, several genes known to regulate proliferation, Foxm1, Skp2, Ezh2, Akt2, and Cdkn1a, are misregulated in islets isolated from these FOXD3 mutant mice. Together, these data place FOXD3 upstream of several pathways critical for β-cell mass expansion in vivo.
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Functional interaction between FOXD3 and Pax3 in cardiac neural crest development.
Genesis (New York N.Y. : 2000), 2010Co-Authors: Brian L. Nelms, Elise R Pfaltzgraff, Patricia A LaboskyAbstract:The transcription factors FOXD3 and Pax3 are important early regulators of neural crest (NC) progenitor cell properties. Homozygous mutations of Pax3 or a homozygous NC-specific deletion of FOXD3 cause marked defects in most NC derivatives, but neither loss of both FOXD3 alleles nor loss of one Pax3 allele alone greatly affects overall development of cardiac NC derivatives. In contrast, compound mutant embryos homozygous for a NC-specific FOXD3 mutation and heterozygous for Pax3 have fully penetrant persistent truncus arteriosus, severe thymus hypoplasia, and midgestation lethality. FOXD3; Pax3 compound mutant embryos have increased cell death in the neural folds and a drastic early reduction of NC cells, with an almost complete absence of NC caudal to the first pharyngeal arch. The genetic interaction between these genes implicates gene dosage-sensitive roles for FOXD3 and Pax3 in cardiac NC progenitors. FOXD3 and Pax3 act together to affect survival and maintenance of cardiac NC progenitors, and loss of these progenitors catastrophically affects key aspects of later cardiovascular development.
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FOXD3 regulates neural crest multipotency and self-renewal
Developmental Biology, 2009Co-Authors: Nathan A. Mundell, Audrey Y. Frist, Patricia A LaboskyAbstract:Concurrent session 4: Neural and tissue specific stem cells Program/Abstract # 29 FOXD3 regulates neural crest multipotency and self-renewal Nathan A. Mundell, Audrey Y. Frist, Patricia A. Labosky Departments of Pharmacology, Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, USA The neural crest (NC) is a specialized group of progenitor cells that arise from the developing spinal cord. At the onset of migration, NC is a heterogeneous pool of multipotent and fate-restricted progenitors that follow regionally defined pathways to sites of differentiation, giving rise to a variety of cell types including neurons, glia, melanocytes, smooth muscle, and cartilage. The forkhead transcription factor FOXD3 is required for self-renewal and maintenance of a multipotent state in two other progenitor cell types: embryonic stem cells and trophoblast stem cells. FOXD3 is also one of the earliest molecular markers of the NC. NC deletion of FOXD3 in the mouse embryo results in severe defects including craniofacial defects, and complete loss of the enteric nervous system. The progenitor pool is depleted and much of the NC is lost by apoptosis in mutant embryos. Lineage labeling of FOXD3 mutant embryos demonstrates that vagal NC fails to migrate into the foregut, and is greatly reduced in the outflow tract of the heart. Surprisingly, reduced cardiac NC mediates cardiovascular remodeling but not parasympathetic innervation of the heart. In vitro clonal analysis of multipotency demonstrates that FOXD3 mutant NC has reduced potency to differentiate into multiple lineages. Serial neurosphere culture experiments indicate that mutant NC does not maintain progenitor self-renewal. These results demonstrate a global role for FOXD3 in NC maintenance along the anteriorposterior axis, and establish the requirement of FOXD3 in maintenance of NC stem cell subpopulations. doi:10.1016/j.ydbio.2009.05.038 Program/Abstract # 30 The role of Gli3 in the neurogenesis of the forebrain Hui Wang, Guannan Ge, Sohyun Ahn Unit on Developmental Neurogenetics, PGD, NICHD, NIH,
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regulation of embryonic stem cell self renewal and pluripotency by FOXD3
Stem Cells, 2008Co-Authors: Ying Liu, Patricia A LaboskyAbstract:The FOXD3 forkhead transcription factor is required for maintaining pluripotent cells in the early mouse embryo and for the establishment of murine embryonic stem cell (ESC) lines. To begin to understand the role of FOXD3 in ESC maintenance, we derived ESC lines from blastocysts that carried two conditional FOXD3 alleles and a tamoxifen-inducible Cre transgene. Tamoxifen treatment produced a rapid and near complete loss of FOXD3 mRNA and protein. FOXD3-deficient ESCs maintained a normal proliferation rate but displayed increased apoptosis, and clonally dispersed ESCs showed a decreased ability to self-renew. Under either self-renewal or differentiation-promoting culture conditions we observed a strong, precocious differentiation of FOXD3 mutant ESCs along multiple lineages, including trophectoderm, endoderm, and mesendoderm. This profound alteration in biological behavior occurred in the face of continued expression of factors known to induce pluripotency, including Oct4, Sox2, and Nanog. We present a model for the role of FOXD3 in repressing differentiation, promoting self-renewal, and maintaining survival of mouse ESCs. Disclosure of potential conflicts of interest is found at the end of this article.
Andrew E. Aplin - One of the best experts on this subject based on the ideXlab platform.
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FOXD3 Modulates Migration through Direct Transcriptional Repression of TWIST1 in Melanoma
Molecular cancer research : MCR, 2014Co-Authors: Michele B. Weiss, Ethan V. Abel, Neda Dadpey, Andrew E. AplinAbstract:The neural crest is a multipotent, highly migratory cell population that gives rise to diverse cell types, including melanocytes. Factors regulating the development of the neural crest and emigration of its cells are likely to influence melanoma metastasis. The transcription factor FOXD3 plays an essential role in premigratory neural crest development and has been implicated in melanoma cell dormancy and response to therapeutics. FOXD3 is downregulated during the migration of the melanocyte lineage from the neural crest, and our previous work supports a role for FOXD3 in suppressing melanoma cell migration and invasion. Alternatively, TWIST1 is known to have promigratory and proinvasive roles in a number of cancers, including melanoma. Using ChIP-seq analysis, TWIST1 was identified as a potential transcriptional target of FOXD3. Mechanistically, FOXD3 directly binds to regions of the TWIST1 gene locus, leading to transcriptional repression of TWIST1 in human mutant BRAF melanoma cells. In addition, depletion of endogenous FOXD3 promotes upregulation of TWIST1 transcripts and protein. Finally, FOXD3 expression leads to a significant decrease in cell migration that can be efficiently reversed by the overexpression of TWIST1. These findings uncover the novel interplay between FOXD3 and TWIST1, which is likely to be important in the melanoma metastatic cascade. Implications: FOXD3 and TWIST1 define distinct subgroups of cells within a heterogeneous tumor. Mol Cancer Res; 12(9); 1314–23. ©2014 AACR.
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Abstract B8: FOXD3 enhances expression of ERBB3 and promotes resistance to vemurafenib
Clinical Cancer Research, 2012Co-Authors: Kevin J. Basile, Ethan V. Abel, Andrew E. AplinAbstract:Melanoma cells driven by mutant B-RAF are sensitive to vemurafenib (PLX4032), which selectively inhibits BRAF/MEK/ERK1/2 signaling. Despite initial tumor shrinkage, most responders in the trials experienced tumor relapse over time. Furthermore, approximately 5–15% of patients show tumor progression. These findings indicate that resistance mechanisms will hamper the clinical efficacy of vemurafenib. We have previously shown that a stemness factor, FOXD3, is upregulated following inhibition of B-RAF-MEK signaling in mutant B-RAF melanoma cells. Here, we show that siRNA-mediated knockdown of FOXD3 significantly enhanced the cell death response after PLX4032 treatment in mutant B-RAF melanoma cell lines. Additionally, ectopic expression of FOXD3 in nonadherent cells significantly reduced cell death in response to PLX4720 treatment. Genome wide analyses revealed that FOXD3 significantly increased expression of ERBB3 through direct binding to a known enhancer region of the ERBB3 gene. Knockdown of endogenous FOXD3 reduced ERBB3 upregulation after treatment with PLX4032. Furthermore, activation of ERBB3 in the presence of ligand was enhanced by B-RAF inhibition in an ERBB2-dependent manner. Treatment with the EGFR/ERBB2 inhibitor, lapatinib, in combination with PLX4032/4720 significantly reduced viability in both in vitro and in vivo assays. These data indicate that upregulation of FOXD3 is an adaptive response to B-RAF inhibitors that enhances ERBB3 signaling and promotes a state of drug resistance.
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FOXD3 Regulates Migration Properties and Rnd3 Expression in Melanoma Cells
Molecular cancer research : MCR, 2011Co-Authors: Pragati Dixit Katiyar, Andrew E. AplinAbstract:The forkhead transcription factor, FOXD3, plays a critical role during development by controlling the lineage specification of neural crest cells. Notably, FOXD3 is highly expressed during the wave of neural crest cell migration that forms peripheral neurons and glial cells but is down-regulated prior to migration of cells that give rise to the melanocytic lineage. Melanoma is the deadliest form of skin cancer and is derived from melanocytes. Recently, we showed that FOXD3 expression is elevated following the targeted inhibition of the B-RAF-MEK-ERK1/2 pathway in mutant B-RAF melanoma cells. Since melanoma cells are highly migratory and invasive in a B-RAF-dependent manner, we explored the role of FOXD3 in these processes. In this study, we show that ectopic FOXD3 expression inhibits the migration, invasion and spheroid outgrowth of mutant B-RAF melanoma cells. Up-regulation of FOXD3 expression following inhibition of B-RAF and MEK correlates with the down-regulation of Rnd3, a Rho GTPase and inhibitor of RhoA-ROCK signaling. Indeed, expression of FOXD3 alone was sufficient to down-regulate Rnd3 expression at the mRNA and protein levels. Mechanistically, FOXD3 was found to be recruited to the Rnd3 promoter. Inhibition of ROCK partially restored migration in FOXD3-expressing cells. These data show that FOXD3 expression down-regulates migration and invasion in melanoma cells and Rnd3, a target known to be involved in these properties.
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Abstract 1067: FOXD3 is a B-RAFV600E-regulated inhibitor of G1/S progression in melanoma cells
Cellular and Molecular Biology, 2010Co-Authors: Ethan V. Abel, Andrew E. AplinAbstract:The forkhead box transcription factor FOXD3 is a stemness factor that prevents the production of melanocyte progenitors from the developing neural crest; however, its role in human cancers is not known. Here we demonstrate that FOXD3 levels are up-regulated following attenuation of B-RAF and MEK signaling in mutant B-RAF harboring human melanoma cells. This effect was selective since FOXD3 was not up-regulated following MEK inhibition in wild-type B-RAF melanoma cells and mutant B-RAF thyroid carcinoma cells. Ectopic FOXD3 expression potently inhibited melanoma cell growth without altering mutant B-RAF activation of ERK1/2. Inhibition of cell growth was due to a potent G1 cell cycle arrest that was largely dependent on p53 and, to a lesser extent, its downstream target p21Cip1. These studies demonstrate that FOXD3 is suppressed by B-RAF, uncover a novel role and mechanism for FOXD3 as a negative cell cycle regulator and have implications for the repression of melanocytic lineage cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1067.
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abstract 1067 FOXD3 is a b rafv600e regulated inhibitor of g1 s progression in melanoma cells
Cancer Research, 2010Co-Authors: Ethan V. Abel, Andrew E. AplinAbstract:The forkhead box transcription factor FOXD3 is a stemness factor that prevents the production of melanocyte progenitors from the developing neural crest; however, its role in human cancers is not known. Here we demonstrate that FOXD3 levels are up-regulated following attenuation of B-RAF and MEK signaling in mutant B-RAF harboring human melanoma cells. This effect was selective since FOXD3 was not up-regulated following MEK inhibition in wild-type B-RAF melanoma cells and mutant B-RAF thyroid carcinoma cells. Ectopic FOXD3 expression potently inhibited melanoma cell growth without altering mutant B-RAF activation of ERK1/2. Inhibition of cell growth was due to a potent G1 cell cycle arrest that was largely dependent on p53 and, to a lesser extent, its downstream target p21Cip1. These studies demonstrate that FOXD3 is suppressed by B-RAF, uncover a novel role and mechanism for FOXD3 as a negative cell cycle regulator and have implications for the repression of melanocytic lineage cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1067.
Dahai Liu - One of the best experts on this subject based on the ideXlab platform.
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inhibition of wnt β catenin signaling by iwr1 induces expression of FOXD3 to promote mouse epiblast stem cell self renewal
Biochemical and Biophysical Research Communications, 2017Co-Authors: Kuisheng Liu, Yuanyuan Sun, Dahai LiuAbstract:Inhibition of Wnt/β-catenin signaling facilitates the derivation of mouse epiblast stem cells (EpiSCs), as well as dramatically promotes EpiSC self-renewal. The specific mechanism, however, is still unclear. Here, we showed that IWR1, a Wnt/β-catenin signaling inhibitor, allowed long-term self-renewal of EpiSCs in serum medium in combination with ROCK inhibitor Y27632. Through transcriptome data analysis, we arrived at a set of candidate transcription factors induced by IWR1. Among these, Forkhead box D3 (FOXD3) was most abundant. Forced expression of FOXD3 could recapitulate the self-renewal-promoting effect of IWR1 in EpiSCs. Conversely, knockdown of FOXD3 profoundly compromised responsiveness to IWR1, causing extinction of pluripotency markers and emergence of differentiation phenotype. FOXD3 thus is necessary and sufficient to mediate self-renewal downstream of Wnt/β-catenin signaling inhibitor. These findings highlight an important role for FOXD3 in regulating EpiSCs and will expand current understanding of the primed pluripotency.
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Inhibition of Wnt/β-catenin signaling by IWR1 induces expression of FOXD3 to promote mouse epiblast stem cell self-renewal.
Biochemical and biophysical research communications, 2017Co-Authors: Kuisheng Liu, Yuanyuan Sun, Dahai LiuAbstract:Inhibition of Wnt/β-catenin signaling facilitates the derivation of mouse epiblast stem cells (EpiSCs), as well as dramatically promotes EpiSC self-renewal. The specific mechanism, however, is still unclear. Here, we showed that IWR1, a Wnt/β-catenin signaling inhibitor, allowed long-term self-renewal of EpiSCs in serum medium in combination with ROCK inhibitor Y27632. Through transcriptome data analysis, we arrived at a set of candidate transcription factors induced by IWR1. Among these, Forkhead box D3 (FOXD3) was most abundant. Forced expression of FOXD3 could recapitulate the self-renewal-promoting effect of IWR1 in EpiSCs. Conversely, knockdown of FOXD3 profoundly compromised responsiveness to IWR1, causing extinction of pluripotency markers and emergence of differentiation phenotype. FOXD3 thus is necessary and sufficient to mediate self-renewal downstream of Wnt/β-catenin signaling inhibitor. These findings highlight an important role for FOXD3 in regulating EpiSCs and will expand current understanding of the primed pluripotency.
Tatjana Sauka-spengler - One of the best experts on this subject based on the ideXlab platform.
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From Pioneer to Repressor: Bimodal FOXD3 Activity Dynamically Remodels Neural Crest Regulatory Landscape In Vivo
Developmental cell, 2018Co-Authors: Martyna Lukoseviciute, Tatiana Hochgreb-hägele, Daria Gavriouchkina, Ruth M. Williams, Upeka Senanayake, Vanessa Chong-morrison, Supat Thongjuea, Emmanouela Repapi, Adam J. Mead, Tatjana Sauka-spenglerAbstract:Summary The neural crest (NC) is a transient embryonic stem cell-like population characterized by its multipotency and broad developmental potential. Here, we perform NC-specific transcriptional and epigenomic profiling of FOXD3-mutant cells in vivo to define the gene regulatory circuits controlling NC specification. Together with global binding analysis obtained by FOXD3 biotin-ChIP and single cell profiles of FOXD3-expressing premigratory NC, our analysis shows that, during early steps of NC formation, FOXD3 acts globally as a pioneer factor to prime the onset of genes regulating NC specification and migration by re-arranging the chromatin landscape, opening cis-regulatory elements and reshuffling nucleosomes. Strikingly, FOXD3 then gradually switches from an activator to its well-described role as a transcriptional repressor and potentially uses differential partners for each role. Taken together, these results demonstrate that FOXD3 acts bimodally in the neural crest as a switch from “permissive” to “repressive” nucleosome and chromatin organization to maintain multipotency and define cell fates.
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From pioneer to repressor: Bimodal FOXD3 activity dynamically remodels neural crest regulatory landscape in vivo
2017Co-Authors: Daria Gavriouchkina, Tatiana Hochgreb-hägele, Ruth M. Williams, Martyna Lukoseviciute, Upeka Senanayake, Vanessa Chong-morrison, Supat Thongjuea, Emmanouela Repapi, Adam J. Mead, Tatjana Sauka-spenglerAbstract:The neural crest (NC) is a transient embryonic stem cell populations characterised by its multipotency and broad developmental potential. Here, we perform NC-specific transcriptional and epigenomic profiling of FOXD3-mutant versus wild-type cells in vivo to define the gene regulatory circuits controlling NC specification. Together with global binding analysis obtained by FOXD3 biotin-ChIP and single cell profiles of FOXD3-expressing premigratory NC, our analysis shows that during early steps of NC formation, FOXD3 acts globally as a pioneer factor to prime the onset of genes regulating NC specification and migration by re-arranging the chromatin landscape, opening cis-regulatory elements and reshuffling nucleosomes. Strikingly, FOXD3 then switches from an activator to its canonical role as a transcriptional repressor. Taken together, these results demonstrate that FOXD3 acts bimodally in the neural crest as a switch from 9permissive9 to 9repressive9 nucleosome/chromatin organisation to maintain 9stemness9 and define cell fates.
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Endogenous FOXD3 in the neural crest is reflected by activity of two enhancers, NC1 and NC2.
2012Co-Authors: Marcos S. Simões-costa, Sonja J Mckeown, Tatjana Sauka-spengler, Joanne Tan-cabugao, Marianne E. BronnerAbstract:(A) Expression of FOXD3 in premigratory neural crest cells at HH8−. (B) At HH8+, FOXD3 expression extends to the midbrain and hindbrain neural folds. (C) At HH9, FOXD3 is expressed by premigratory and migrating neural crest cells, at cranial, vagal and trunk levels with the exception of rhombomere 3 (dotted arrow). (D) FOXD3 transcripts are detected in migrating cranial crest cells at stage HH10. (E–F) Double fluorescent in situ hybridization for Sox10 (red) and FOXD3 (green) reveals differences in the expression domains of these neural crest specifiers at stages HH9 (E) and HH10 (F). Expression of Sox10 begins only as cells leave the neural tube at all axial levels. (G–H) Expression of eGFP driven by enhancer NC1 at stages HH8+ and HH10. Bar indicates approximate level of transverse section shown in L. (I) In situ hybridization of FOXD3 at stage HH12. (J) Expression of eGFP driven by enhancer NC1. (K) eGFP driven by enhancer NC2. (L–N) Transverse sections through embryos shown in H, J, K. Arrows indicate migratory neural crest expressing eGFP. HNK-1-positive cells shown are in blue in M and N. (O) Genomic region of FOXD3 in chick showing regions tested for enhancer activity between the flanking genes Atg4c and Alg6 (blue boxes). Boxes indicate regions that were tested for enhancer activity: black boxes indicate no detectable activity in the neural crest; green boxes indicate enhancers active in the neural crest. Coding regions are indicated by blue boxes. anf: anterior neural fold, not: notochord, nf: neural fold, nc: neural crest, ncc: neural crest cells, nt: neural tube, ot: otic placode, R: rhombomere.
Tatiana Hochgreb-hägele - One of the best experts on this subject based on the ideXlab platform.
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From Pioneer to Repressor: Bimodal FOXD3 Activity Dynamically Remodels Neural Crest Regulatory Landscape In Vivo
Developmental cell, 2018Co-Authors: Martyna Lukoseviciute, Tatiana Hochgreb-hägele, Daria Gavriouchkina, Ruth M. Williams, Upeka Senanayake, Vanessa Chong-morrison, Supat Thongjuea, Emmanouela Repapi, Adam J. Mead, Tatjana Sauka-spenglerAbstract:Summary The neural crest (NC) is a transient embryonic stem cell-like population characterized by its multipotency and broad developmental potential. Here, we perform NC-specific transcriptional and epigenomic profiling of FOXD3-mutant cells in vivo to define the gene regulatory circuits controlling NC specification. Together with global binding analysis obtained by FOXD3 biotin-ChIP and single cell profiles of FOXD3-expressing premigratory NC, our analysis shows that, during early steps of NC formation, FOXD3 acts globally as a pioneer factor to prime the onset of genes regulating NC specification and migration by re-arranging the chromatin landscape, opening cis-regulatory elements and reshuffling nucleosomes. Strikingly, FOXD3 then gradually switches from an activator to its well-described role as a transcriptional repressor and potentially uses differential partners for each role. Taken together, these results demonstrate that FOXD3 acts bimodally in the neural crest as a switch from “permissive” to “repressive” nucleosome and chromatin organization to maintain multipotency and define cell fates.
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From pioneer to repressor: Bimodal FOXD3 activity dynamically remodels neural crest regulatory landscape in vivo
2017Co-Authors: Daria Gavriouchkina, Tatiana Hochgreb-hägele, Ruth M. Williams, Martyna Lukoseviciute, Upeka Senanayake, Vanessa Chong-morrison, Supat Thongjuea, Emmanouela Repapi, Adam J. Mead, Tatjana Sauka-spenglerAbstract:The neural crest (NC) is a transient embryonic stem cell populations characterised by its multipotency and broad developmental potential. Here, we perform NC-specific transcriptional and epigenomic profiling of FOXD3-mutant versus wild-type cells in vivo to define the gene regulatory circuits controlling NC specification. Together with global binding analysis obtained by FOXD3 biotin-ChIP and single cell profiles of FOXD3-expressing premigratory NC, our analysis shows that during early steps of NC formation, FOXD3 acts globally as a pioneer factor to prime the onset of genes regulating NC specification and migration by re-arranging the chromatin landscape, opening cis-regulatory elements and reshuffling nucleosomes. Strikingly, FOXD3 then switches from an activator to its canonical role as a transcriptional repressor. Taken together, these results demonstrate that FOXD3 acts bimodally in the neural crest as a switch from 9permissive9 to 9repressive9 nucleosome/chromatin organisation to maintain 9stemness9 and define cell fates.
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A novel FOXD3 gene trap line reveals neural crest precursor movement and a role for FOXD3 in their specification.
Developmental biology, 2012Co-Authors: Tatiana Hochgreb-hägele, Marianne E. BronnerAbstract:Neural crest cells migrate extensively and contribute to diverse derivatives, including the craniofacial skeleton, peripheral neurons and glia, and pigment cells. Although several transgenic lines label neural crest subpopulations, few are suited for studying early events in neural crest development. Here, we present a zebrafish gene/protein trap line gt(FOXD3-citrine)^(ct110a) that expresses a Citrine fusion protein with FOXD3, a transcription factor expressed in premigratory and migrating neural crest cells. In this novel line, citrine expression exactly parallels endogenous FOXD3 expression. High-resolution time-lapse imaging reveals the dynamic phases of precursor and migratory neural crest cell movements from the neural keel stage to times of active cell migration. In addition, Cre-recombination produces a variant line FOXD3-mCherry-pA whose homozygosis generates a FOXD3 mutant. Taking advantage of the endogenously regulated expression of FOXD3-mCherry fusion protein, we directly assess early effects of FOXD3 loss-of-function on specification and morphogenesis of dorsal root ganglia, craniofacial skeleton and melanophores. These novel lines provide new insights and useful new tools for studying specification, migration and differentiation of neural crest cells.
